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Biochemical manifestation of inborn error

How do you recognize a

metabolic disorder ??

III – Phenylalanine & Tyrosine metabolic disorders:

The clinical features

  • irritability, feeding problems, vomiting in the first few weeks of life,
  • mental retardation,
  • generalized eczema and reduced melanine formation.
  • mousey odor urine

An inherited deficiency of liver homogentisic acid oxidase with accumulation of homogentisic acid in blood, tissues and urine.

Oxidation and polymerization of this substance produces the alkapton pigment.

The clinical features

  • arthritis
  • black urine or urine becomes dark on standing in air.

An inherited deficiency of tyrosinase enzyme in melanocytes causes one form of albinism.

The clinical features

  • lacks melanin pigment in skin, hair and iris
  • acute photosensitivity.

I - Glycine meta bolic disorders

a – Cystinuria (Cystine-Lysinuria):

b – Cystinosos (Cystine storage disease):

c – Homocystinuria

Clinical features

  • mental retardation,
  • osteoporosis,
  • thrombosis
  • dislocated lenses.

Hartnup disease:

There a renal and intestinal transport defect involving neutral amino acids with increased urinary loss of tryptophan.

Tryptophan is normally partly converted to nicotinamide.

The clinical features

  • Resemble those of pellagra, namely: a red, scaly rash on exposed areas of skin
  • Mental confusion
  • Excessive amounts of indol compounds in the urine that arise from intestinal bacteria degradation of unabsorbed tryptophan.

Maple syrup urine disease:

There is a deficient decarboxylation of the -ketoacids resulting from deamination of the three branched-chain amino acids, leucine, isoleucine and valine.

Plasma and urinary levels of these amino acids and their -ketoacids are elevated.

  • Increased ketoacids -> ketosis, metabolic acidosis
  • Increased glucose utilization -> ketosis
  • Increased leucine -> brain toxicity

The clinical features

  • maple syrup or burnt sugar odour of the urine
  • the disease presents in the first week of life and if untreated, severe neurological lesions develop with death in a few months.

Disorders of the amino acid metabolism

R.N. sadeghi

Introduction

Some metabolic disorders of amino acids

I -Glycine metabolic disorders

II –Sulpher-containing amino acids disorders

III –Phe & Tyr metabolic disorders

IV –Natural amino metabolic disorders

V –Disorders of branched-chain amino acids

What is a metabolic disease?

V – Metabolic disorders of branched-chain amino acids metabolism:

Disorders of the amino acid metabolism

  • single gene mutations

> the defective or absent protein is an enzyme (Most of these inborn disorders)

> The defective or absent protein is involved it transport processes as cystinuria and Hartnup diseases.

“Inborn errors of metabolism”

Clinical manifestation

  • the accumulation of substrate.
  • reduction of the product
  • diversion of intermediates
  • failure of transport mechanisms.

The clinical presentation of inborn error

  • is often non-specific
  • In an infant the symptoms may include
  • poor feeding
  • lethargy
  • vomiting

which are seen in any illness

  • older children, failure to thrive or developmental delay may be the only presentation

II – Sulpher-containing amino acids metabolic disorders:

IV – Natural amino metabolic disorders

a - Glycinuria

It is characterized by excessive urinary excretion of glycine and plasma glycine level is normal. It results from a defect in renal tubular reabsorption

b – Primary hyperoxaluria:

Tryptophan

Intestinal Lumen

Niacin

Tryptophan

NADP

Cytoplasm

= Symptoms:

  • Skin lesions
  • Rash
  • Pigmentation changes
  • Diarrhoea
  • Photosensitivity

It is characterized by excessive urinary excretion of oxalate that unrelated to dietary intake of oxalate in diet.

a – Phenylketonuria (PKU)

Clinical features :

  • Phenylalanine accumulates in the blood and is excreted in the urine together with its derivatives such as phenyl pyruvate, phenyl lactate and phenyl acetate.
  • The disease acquires its name from the recognition of these derivatives in the urine.
  • Progressive bilateral urolithiasis
  • Nephrocalcinosis
  • Recurrent infection of the urinary tract
  • Rrenal failure

b – Alkaptonuria

c – Albinism

Physical examination

History

  • General – dymorphism
  • Odor
  • Maple syrup smell in Maple syrup urine disease
  • Musty smell in phenylketonuria;
  • Fish smell in trimethyl aminuria
  • Cabbage smell in hypermethioninaemia

Timing of onset of symptoms

after feeds were started

Laboratory

  • Glucose
  • Electrolytes
  • Gas
  • Ketones
  • BUN
  • Creatinine
  • Lactate
  • Ammonia
  • Bilirubin
  • ...........

Family History

Index of suspicion

  • parents are cousins
  • ethnicity
  • neonatal deaths, fetal losses
  • maternal family history

> Many of these genetic disorders result in irreversible brain damage and early mortality.

>Treatment

  • Dietary Restriction
  • Supplement deficient product
  • Stimulate alternate pathway
  • Supply vitamin co-factor
  • Organ transplantation
  • Enzyme replacement therapy
  • Gene Therapy

  • Family History
  • History
  • Physical examination
  • Laboratory

Mental Retardation

Visual Distubances

Photophobia

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